Synthesis and biological activity of a novel class of pyridazine analogues as non-competitive reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B).

A series of novel pyridazine analogues were prepared and the structure-activity relationship of their behavior as inhibitors of PTP1B was evaluated. Most of the analogues had potencies in the low micromolar range. The in vitro kinetics of this compound series demonstrated that they were reversible non-competitive binders. This indicates that there may exist another site in the enzyme through which enzyme activity can be inhibited, which is not a recognized interaction domain. Some of the analogues exhibited high selectivity for other PTPases, for example, compound 12 mp showed 20-fold selectivity for PTP1B (IC50=5.6 microM) versus both TCPTP and LAR (>100 microM, respectively). In contrast to many tyrosine phosphatase mimetic inhibitors, this compound class lacks negative charge and thus showed high permeability across cell membranes. Selective analogues in the series were analyzed in an in vitro cellular assay, which showed increased insulin-stimulated insulin receptor phosphorylation.

Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1.

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.